Willardsen M et al. (2014), The ETS transcription factor Etv1 mediates FGF ...

XB-ART-47781

Mech Dev 2014 Feb 01;131:57-67. doi: 10.1016/j.mod.2013.10.003.

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The ETS transcription factor Etv1 mediates FGF signaling to initiate proneural gene expression during Xenopus laevis retinal development.

Willardsen M , Hutcheson DA , Moore KB , Vetter ML .

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Fibroblast growth factor signaling plays a significant role in the developing eye, regulating both patterning and neurogenesis. Members of the Pea3/Etv4-subfamily of ETS-domain transcription factors (Etv1, Etv4, and Etv5) are transcriptional activators that are downstream targets of FGF/MAPK signaling, but whether they are required for eye development is unknown. We show that in the developing Xenopus laevis retina, etv1 is transiently expressed at the onset of retinal neurogenesis. We found that etv1 is not required for eye specification, but is required for the expression of atonal-related proneural bHLH transcription factors, and is also required for retinal neuron differentiation. Using transgenic reporters we show that the distal atoh7 enhancer, which is required for the initiation of atoh7 expression in the Xenopus retina, is responsive to both FGF signaling and etv1 expression. Thus, we conclude that Etv1 acts downstream of FGF signaling to regulate the initiation of neurogenesis in the Xenopus retina.

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Species referenced: Xenopus laevis
Genes referenced: ascl3 atoh7 etv1 etv4 fzd5 mapk1 neurod1 neurog1 neurog2 pax6 rax sox2
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	Fig. 1. Expression of etv1 in the developing Xenopus laevis eye. Etv1 is detected by whole mount in situ hybridization during optic vesicle evagination (A, anterior view – bracket; inset, lateral view – arrow), in the pre-neurogenic optic vesicle (B, anterior view – bracket; inset, lateral view – arrow), and during the initial stages of retinal neurogenesis, (C and D, lateral view). By stage 29–30, etv1 is only expressed in the developing lens vesicle (E, lateral view – arrowhead). In situ hybridization on sections shows etv1 is most highly expressed in the ventral stalk and ventral optic vesicle at stage 24, with weaker expression in the neuroepithelium of the central to dorsal optic vesicle, and overlying surface ectoderm (F). At stage 28, etv1 is expressed throughout the retinal neuroepithelium and overlying surface ectoderm (G). At stage 29–30, the developing lens vesicle is strongly labeled, while there is no detectable expression of etv1 in the developing neural retina (H). At the end of embryonic retinal neurogenesis, etv1 is expressed in the photoreceptors of the outer nuclear layer but is absent from the rest of the central retina and also from progenitors in the ciliary marginal zone (I). Abbreviations: ov, optic vesicle; e, eye; lv, lens vesicle; se, surface ectoderm; ne, neuroepithelium; os, optic stalk; nr, neural retina; cmz, ciliary marginal zone; onl, outer nuclear layer.
	Fig. 2. Loss of Etv1 function prevents proneural gene expression. Etv1 function was blocked by injection of etv1 MO at the 8-cell stage (B,E,H,K,N,Q,T) or by transgenic expression of dnEtv1 using the eye-specific enhancer for human fzd5 (C,F,I,L,O,R,U). In situ hybridization on stage 28 embryos showed that expression of early retinal markers were unaffected relative to the uninjected side, including rax (A and B, n = 78/82 unaffected; C, n = 32/32), pax6 (D and E, n = 59/65; F, n = 15/15), sox2 (G and H, n = 51/58; I, n = 28/28), and the pre-neurogenesis bHLH gene ascl3 (J and K n = 37/37; L, n = 32/32). Expression of proneural bHLH genes required for retinal neurogenesis was reduced compared to the uninjected side: atoh7 (M and N, n = 70/124 reduced; O, n = 56/98), neurog2 (P and Q, n = 39/61; R, n = 20/34), and neurod1 (S and T, n = 53/103; U, n = 18/28). Arrows indicate the eye.
	Fig. 5. Etv1 overexpression does not trigger early retinal neurogenesis. Early retinal patterning genes rax (A–C) and pax6 (D–F) were unaffected by 8-cell injection of mRNA for etv1. The proneural bHLH gene atoh7 (G, n = 49) and neurod1 (J, n = 76) were not expressed prematurely at stage22/23, indicating that etv1 was insufficient to initiate their expression. At stage 28, expression of both atoh7 (H and I) and neurod1 (K and L) was reduced on the injected side compared to the uninjected side (n = 24/48 for atoh7; n = 20/34 for neurod1). Arrows indicate the eye.

References [+] :

Agathocleous, A directional Wnt/beta-catenin-Sox2-proneural pathway regulates the transition from proliferation to differentiation in the Xenopus retina. 2009, Pubmed, Xenbase